16beta-alkylthio-17-oxo-steroids



United States Patent 3,381,002 16,8-ALKYLTHIO-17-0X0-STEROIDS Taichiro Komeno, Osaka, and Norio Tokutake, Kobe, Japan, assignors to Shionogi & Co., Ltd., Osaka, Japan No Drawing. Filed Mar. 1, 1963, Ser. No. 262,212

Claims priority, application Japan, Mar. 20, 1962,

37/ 11,348 17 Claims. (Cl. 260239.55)

The present invention relates to steroid and production thereof. More particularly, it relates to 16,8-alkylthio-17- oxo-steroid and production thereof.

The process of the present invention is substantially representable by the following scheme:

wherein X is a halogen atom (e.g chlorine, bromine, iodine); R is a lower alkyl group (e.g. methyl, ethyl, propyl, butyl, pentyl, hexyl); and the ripple mark (2) represents 04- or B-configuration.

The process may be generally applicable to the conversion of a 16-halogeno-17-oxo-steroid into the corresponding 16/8-alkylthio-17-oxo-steroid. Especially, its application to the 16-halogeno-17-oxo-steroid represented by the formula:

wherein X has the same significance as designated above; a substituent(s) such as hydroxyl, lower alkanoyloxy (e.g. acetyloxy, propionyloxy, butyryloxy), oxo, lower alkylenedioxy (e.g. ethylenedioxy, propylenedioxy), lower alkyl (e.g. methyl, ethyl, propyl) and lower alkoxy (e.g. methoxy, ethoxy, propoxy) and less than 4 double bond(s) can be present at any position(s) on the A-ring and the A- and B-rings, respectively; and the ripple mark (5) represents ocor ,B-configuration, gives the correspondwherein R has the same significance as designated above; and a substituent(s) such as hydroxyl, lower alkanoyloxy (e.g. acetyloxy, propionyloxy, butyryloxy), oxo, lower alkylenedioxy (e.g. ethylenedioxy, propylenedioxy), lower alkyl (e.g. methyl, ethyl, propyl) and lower alkoxy (e.g. methoxy, ethoxy, propoxy) and less than 4 double bond(s) can be present at any position(s) on the A-ring and the A- and B-rings, respectively, which may possess physiological activities. Accordingly, the process of the present invention will be hereinafter illustrated taking its application to the said 16-halogeno-17-oxo-steroid (I) as an example. However, it should be understood that the scope of the present invention is not limited only to the application of the process to the said 16-halogeno-17-oxosteroid (I).

When the process of the present invention is applied to the 16-halogeno-17-oxo-steroid (I), the conversion may be represented by the formula:

W R SR C D C D Thioetherification wherein X and R each has the same significance as designated above; a substituent(s) such as hydroxyl, lower alkanoyloxy (e.g. acetyloxy, propionyloxy, butyryloxy), oxo, lower alkylenedioxy (e.g. ethylenedioxy, propylenedioxy), lower alkyl (e.g. methyl, ethyl, propyl) and lower alkoxy (e.g. methoxy, ethoxy, propoxy) and less than 4 double bond(s) can be present at any position(s) on the A-ring and the A- and B-rings, respectively; and the ripple mark (i) represents Otor fi-configuration.

The starting materials, 16-halogeno-17-oxo-steroids (I), may be exemplified as follows:

16a-chloroestrone,

16 tx-bromoestrone,

16,8-bromoestrone,

16a-bromoestrone 3-methyl ether,

16/8-bromoestrone 3-ethy1 ether,

l-methyl- 1 6a-chloroestrone,

l-methyl-l 6 S-br0moestrone,

l-methyl- 1 fiwbromoestrone 3-methyl ether, 4-methyl-16a-chloro-1,3,5(10)-estratrien-17-one, 4-methyl-16tx-bromo-L3 ,5 10) -estratrien-17-one,

3 u-hydroxy-l 6u-chloro-5 8-androstan-17-one,

3 a-hydroxy-l 6a-bromo-5fi-androstan-17-one, 3 3-hydroXy-16a-bromo-5a-androstan-17-0ne,

3 a-hydroxy-16B-bromo-5B-androstan-17-one, 3,8-hydroxy-16a-bromo-5tx-androstan-17-one 3 -acetate, 3/8-hydroXy-16ot-bromo-5 (6 androsten-17-one, 3B-hydroxy-16a-bromo-5(6)-androsten-1 7-one 3-acetate, 3 CC-hYdI'OXY-16}3-10dO-5(6)-aHdIOStI1-17-0118 3-acetate, 3 B-hydroxy- 1 6B-bromo-5 6 -androsten-17 -one,

3 B-hydroxyl 6/3-bromo-5 6) -androsten- 17-one 3-acetate, 16tx-ch1oro-5/3-androstane-3 ,17-dione,

16a-b1OInO-5 ot-androstane-Ci ,17-dione, 16 3bromo-5/3-androstane-3,17-dione, l6OL-Ch1OI'O-4-21I1d1'OSteI1C-3,17-dl011e, 16a-bromo-4-androstene-3,17-dione,

3 ,3-ethylenedioXy-1 6/3-bromo-5 (6) -androsten- 17-one,

etc.

The said 16-halogeno-17-oxo-steroids (I) are known compounds and/ or can be prepared according to per se conventional manners [e.g., Fried et al.: US. Patent Nos. 2,857,403 and 2,831,872; Ellis et al.: J. Chem. 800., p. 800 (1958); *Fajkos et al.: Chemical Abstracts, vol. 53, p. 4349 (1959); Johnson et al.: I. Am. Chem. Soc., vol. 79, p. 2005 (1957)].

According to the process of the present invention, the 16-halogeno-17-oXo-steroid (I) is reacted substantially with a metal lower alkylmercaptide, preferably an alkali metal lower alkylmercaptide (e.g. sodium 'methylmercaptide, sodium ethylmercaptide, potassium methylmercaptide, potassium ethylmercaptide), to obtain the 16B-1ower alkylthio-17-oxo-steroid (II). The reaction may proceed by treating the 16-halogeno-17-oXo-steroid (I) with a metal lower alkylmercaptide in an inert organic solvent medium (e.g. acetone, dioxane, ether, tetrahydrofuran) at a temperature from room temperature (15 to 30 C.) to reflux temperature, if necessary, while stirring. Instead of the metal lower alkylmercaptide, there may :be employed a combination of a lower alkylmercaptan (e.g. methylmercaptan, ethylmercaptan, propylmercaptan) and an alkali metal salt (e.g. sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate). Hereupon, the lower alkylthio group at the 16-position of the product (II) always takes S -configuration, regardless of the configuration of the halogen atom at the 16-posi tion of the starting material (I).

The thus-produced l6fi-lower alkylthio-17-oxo-steroid (II) is specifically exemplified as follows:

16fl-methylthioestrone,

16fl-ethylthioestrone,

165-propylthioestrone,

16fi-butylthioestrone,

l6fi-ethylthioestrone 3-methyl ether, 16,8-ethylthioestrone 3-ethyl ether, 1618-butylthioestrone B-methyl ether, l-methyl-l6fl-ethy1thioestrone,

l-methyl-l 6,8-ethylthioestrone 3 -methyl ether, l-methyl- 1 6fl-butylthioestrone 3 -methyl ether, 4-methyl-16 3-methylthio-1,3,5 -estratrien-17-one, 4-methyl-16,9-ethylthio-l,3,5( 10) -estratrien-17-one, 4-methyl-16fl-butylthio-1,3,5 10) -estratn'en-l7-one, 3a-hydroxy-l6fi-ethylthio-5fi-androstan-17-one, 3fl-hydroxy-16,8-ethy1thio-5a-androstan-17-one,

'3 fi-hydroxy-16B-ethylthio-5 (6) -androsten-17-one, 3a-hyd-roxy-16,8-ethylthio-5 (6 -androsten-17-one, 16fl-ethylthio-SB-androstan-S, 17 -dione, 16fi-methylthio-5a-androstan-3 ,17-dione, 16fi-ethylthio-4-androstene-3, l7-dione, 3,3-ethylenedioxy-16;3-ethylthio-5 (6) -androsten-17-one,

etc.

These products (II) generally show various physiological activities such as pituitary gonadotrophin inhibiting activity, lipid shifting activity, uterotropic activity and anti-DOCA (desoxycorticosterine acetate) activity. For instance, 16fl-ethylthioestrone 3-methyl ether showed significant pituitary gonadotrophin inhibitory activity at the oral dosage of 10 milligrams in the test using mice. Further, for instance, 3fi-hydroxy-l65-ethylthio-5(6)-androsten-17'one 3-acetate inhibited the depletion of urinary volume and Na retention caused by DOCA, when subcutaneously administered to rats. The other products possess the similar physiological activities. Accordingly, they are useful as artificial hormonic agents.

The following examples set forth illustratively presently-preferred embodiments of the invention. In these examples, the abbreviations are intended to have conventional meaning: e.g. g., gram(s); mg., milligram(s); ml., millilitre(s); C., degrees centigrade.

Example 1 To a solution of lfia-bromoestrone 3-methy1 ether [Johnson et 21.: J. Am. Chem. Soc., vol. 79, p. 2005 (1957)] (728 mg.) in anhydrous acetone (28 ml.), there is added potassium ethylmercaptide (300 mg.) while stirring at room temperature to 30 C.). After stirring for 40 minutes, water is added to the reaction mixture and then shaken with ether. The ether extract is washed with 5% sodium hydroxide and water in order, dried over potassium carbonate and evaporated to give a yellowish viscous substance (661 mg.). The substance is dissolved in ethanol, treated with activated carbon and condensed to separate crude crystals (237 mg.) melting at C. The mother liquor is chromatographed on alumina and eluted with a mixture of petroleum ether and benzene (1:1) to give additional crude crystals (219 mg). These crystals are combined together and recrystallized from methanol to give l6 8-ethylthioestrone S-methyl ether (430 mg.) as White plates melting at C. [a] +109.2 (CHCl A333,? m (e): 221 (8,600), 278.5 (1,930), 287 (1,810), 322 (172). 11:35,? 1726 cm.-

Analysis.Calcd. for C H O S: C, 73.21; H, 8.22;

S, 9.31. Found: C, 72.84; H, 8.19; S, 9.34.

Example 2 o I I1 I SGH To a suspension of 16a-bron10estrone 3-methyl ether (2 g.) in anhydrous acetone ml), there is added potassium butylmercaptide (1.2 g.), and the resultant mixture is stirred for 2 hours at room temperature (15 to 30 C.). Water is added to the reaction mixture and then shaken with ether. The ether extract is washed with water, dried and evaporated to give the residue (2.28 g.), The residue is chromatographcd on alumina (120 g.) and eluted with a mixture of petroleum ether and benzene (1:1). The eluate is evaporated and crystallized from methanol to give 16p-butylthioestrone 3-methyl ether (1.26 g.) as colorless prisms melting at 107.5 to 108.5 C. +94.4 (CHCl A3523? m (e): 221.6 (9,490), 278 (2,190), 287 (2,020), 321 v23? 1729, 1610, 1503, 1256, 1236 cm.'

Analysis.-Calcd. for C H O S: C, 74.15; H, 8.66;

S, 8.61. Found: C, 74.26; H, 8.62; S, 8.70.

SCzHa 0 o L, L.

A mixture of 3,3-ethylenedioxy-16fl-bromo-5(6)-androsten-17-one (1.000 g.), prepared by subjecting 16B- bromo-4-androstene-3,17-dione [Fajkos et al.: Chemical Abstracts, vol. 53, p. 4349 (1959)] to ketalation with ethylene glycol and p-toluenesulfonic acid' in a per se conventional manner, and sodium ethylmercaptide (450 mg.) in acetone (20 ml.) is stirred for 3 hours at room temperature (15 to 30 C.). Water is added to the reaction mixture, and the precipitate is collected by filtration, washed with water and dried. The resultant substance is chromatographed on alumina (20 g.) and eluted with a mixture of petroleum ether and benzene (2:1). After recovery of the starting material (212 mg), the subsequent eluate is evaporated and recrystallized from methanol to give 3,3 ethylenedioxy 16B ethylthio 5(6) androsten-l7-one (435 mg.) as scales melting at 164 to 166 C. [111 5.9:2 (CHCl li" 733, 1670 cm.-

Analysis.-Calcd. for C H O S: C, 70.73; H, 8.77; S, 8.21. Found: C, 70.79; H, 8.76; S, 8.04.

Example 4 16fi bromo-4-androstene-3,17-dione is subjected to thioetherification as in Example 3 to give 16fi-ethy1thio-4-androstene-3,17-dione as pillars melting at 153 to 155 C.

(crystallized from methanol). [u] +ll5.8:!:2 (CHCl A222? my (6): 241 (17,560). 11:21? 1736, 1662, 1616 cm."

Analysis.-Calcd. for C H O S: C, 72.78; H, 8.73; S, 9.25. Found: C, 72.95; H, 8.85; S, 9.31.

Example 5 sour; $113 $H: CHaOx/ CHaO 1133 1739, 1606, 1586 cm. The starting material of this example, l-methyl-lfiabromoestrone 3-methy1 ether, is prepared from testosterone propionate according to the following scheme:

OCOC2H Bromine Acetic acid OCOC2H Collidine OCOCzHs Acetic anhydride p-Toluenesulfonic acid OCOCzH;

I Palladium-carbon 0113000 Hydwgen (1) Potassium hydroxide Methanol CH3 COO Potassium hydroxide H Chromic ac d Isopropenyl acetate I Sulllll'lC acid OHaO Gaol ll Example 6 CHsCOO i/ CHsCOO A mixture of 3 3-hydroxy-l6B-bromo-5(6)-androsten- 17-one 3-acetate [Ellis et al.: J. Chem. Soc., p. 800 (1958)], (2.05 g.), potassium carbonate (485 mg), ethylmercaptan (0.75 ml.) in acetone (20 ml.) is refluxed for 3 hours while stirring and then allowed to stand at room temperature (15 to 30 C.), overnight. Water is added to the reaction mixture and shaken with ether. The ether extract is washed with 5% sodium hydroxide and water in order, dried over potassium carbonate and evaporated. The residue is chromatographed on alumina (40 g.) and eluted with a mixture of petroleum ether and benzene to give crude crystals (904 mg.) melting at 115 to 120 C. The crude crystals are recrystallized from methanol to give 3fi-hydroxy-l6B-ethylthio-5(6) androsten-17-one 3-acetate as pillars melting at 124 to 126 C.

[a] 24.4:l:2 (01101 1738 (shoulder) 1728,

1243, 1036 emf Analysis.Calcd. for C H O S: C, 70.73; H, 8.77; S, 8.21. Found: C, 70.73; H, 8.85; S, 8.06.

Example 7 CHsCOO CzHl A mixture of SB-hydroxy-lfi bromo-S(6)-and=rosten- 17-one S-acetate (1.000 g.) and sodium ethylmercaptide (411 mg.) in acetone (25 ml.) is stirred for 3 hours at room temperature 15 to 30 S.). Water is added to the reaction mixture and shaken with ether. The ether extract is washed with sodium hydroxide and water in order, dried over potassium carbonate and evaporated. The residue is chromatographed on alumina and eluted with a mixture of petroleum ether and benzene. The eluted substance is crystallized from pentane to give 3 3-hydroxy- 16fi-ethylthio-5(6)-androsten-17-one 3-acetate (560 mg.) as pillars melting at 124 to 126 C.

In the similar manner, there can be obtained other 163- lower alkylthioestrone lower alkyl ether, 3,3-lower alkylene dioxy 16B lower alkylthio 5(6) androstenl7-one, 16fi-lower alkylthio-4-androstene-3,17-dione, 1- lower alky1-16p-lower alkylthioestrone lower alkyl ether and BB-hydroxy-lGfl-lower alkylthio-S(6)-androsten-l7- one 3-lower alkanoate.

8, What is claimed is: 1. Process which comprises reacting 16-halogeno-17- oxosteroid of the formula wherein X is a halogen selected from the group consisting of Cl, Br and I, and Z is a ring system selected from the group consisting of alkyl and lower alkanoyl-O I lower alka11oy1-O-- with metal lower alkylmercaptide to produce the corresponding 16fi-lower alkylthio-17-oxo-steroid.

2. Process according to claim 1, wherein the metal lower alkyl mercaptide is alkali metal lower alkylmercaptide.

3. Process according to claim 1, wherein the reaction is carried out in an inert organic solvent.

4. Process according to claim 1, wherein the reaction is carried out at a temperature from room temperature to reflux temperature.

5. A steroid of the formula:

wherein R is a lower alkyl group and Z is a ring system selected from the group consisting of lower alkyl lower alkyl-Om l f O 0 and lower alkanoyl-O lower alkanoyl-O 6. 16,8-lower alkylthioestrone lower alkyl ether. 7. 16fl-ethylthioestrone 3-methyl ether. 8. l6fl-butylthioestrone 3-methyl ether.

lower alkyl-0 9. 3,3-1ower alkylenedioxy-16B-lower a1ky1thi0-5(6)- 16. 3 3 hydroxy 16B ethylthio 5(6) androstenandrosten-17-one. 17-one 3-acetate.

10. 3,3 ethylenedioxy 16,8 ethylthio 5 (6) an- 17. 3,3-thylenedioxy- 16,8 -10Wer alkylthio 5(6) andr0sten-17-one. drosten-17-0ne.

11. 16B-10Wer a1ky1thi04-andr0stene-3,17-di0ne. 5 References Cited 12. 1613-ethylthio-4-androstene-3,17-dione.

13. 1 lower alkyl 16;? -lower alkylthioestrone lower UNITED STATES PATENTS alkyl ethen 2,837,464 6/1958 Nobfle 260-397.47

14. l-methyl-l6p-ethylthioestrone B-methyl ether. 15. 3,8-hydroxy-16B-lower alkylthio-S(6)-androsten-17- 10 ELBERT ROBERTS Pnmary Examl'ler' one 3-1ower alkanoate. L. GOTTS, Examiner. 

1. PROCESS WHICH COMPRISES REACTING 16-HALOGENO-17OXO-STEROID OF THE FORMULA
 5. A STEROID OF THE FORMULA: 